Method of treating diabetes mellitus in a patient

ABSTRACT

The need for the delivery of insulin by injection can be reduced or eliminated by delivering an aerosolized monomeric insulin formulation. Repeatability of dosing and more particularly the repeatability of the blood concentration versus time profile are improved relative to regular insulin. The blood concentration versus time profile is substantially unaffected by specific aspects of the patient&#39;s breathing maneuver at delivery. Further, the rate at which blood glucose is lowered is increased by the use of monomeric insulin. Particles of insulin and in particular monomeric insulin delivered to the surface of lung tissue will be absorbed into the circulatory system. The monomeric insulin may be a dry powder but is preferably in a liquid formulation delivered to the patient from a hand-held, self-contained device which automatically releases an aerosolized burst of formulation. The device includes a sensor which is preferably electronic which measures inspiratory flow and volume which measurement can be used to control the point of drug release.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of application Ser. No.09/656,535, filed Sep. 7, 2000, which is a continuation of applicationSer. No. 09/004,756, filed Jan. 8, 1998 (now U.S. Pat. No. 6,131,567issued on Oct. 17, 2000), which is a continuation-in-part of applicationSer. No. 08/792,616, filed Jan. 31, 1997 (now U.S. Pat. 5,888,477 issuedon Mar. 30, 1999), which is a continuation-in-part of application Ser.No. 08/754,423 filed Nov. 22, 1996 (now U.S. Pat. No. 5,743,250 issuedon Apr. 28, 1998), which is a continuation-in-part of application Ser.No. 08/549,343, filed on Oct. 27,1995 and issued as U.S. Pat. No.5,915,378 on DATE, which is a continuation-in-part of application Ser.No. 08/331,056 filed Oct. 28, 1994 and issued as U.S. Pat. No. 5,672,581on Sep. 30, 1997, which is a continuation-in-part of application Ser.No. 08/011,281, filed on Jan. 29, 1993 and issued as U.S. Pat. No.5,364,838 on Nov. 15, 1994 all of which are incorporated herein byreference and to which application we claim priority under 35 U.S.C.§120.

FIELD OF THE INVENTION

[0002] This invention relates generally to a method of aerosolized drugdelivery. More specifically, this invention relates to the controlledintrapulmonary delivery of a monomeric insulin alone or in combinationwith other treatment methodologies which are combined to significantlyreduce or eliminate the need for administering insulin by injection.

BACKGROUND OF THE INVENTION

[0003] Diabetes Mellitus is a disease affecting approximately 7.5million people in the United States. The underlying cause of thisdisease is diminished or absent insulin production by the Islets ofLangerhans in the pancreas. Of the 7.5 million diagnosed diabetics inthe United States, approximately one-third are treated using insulinreplacement therapy. Those patients receiving insulin typicallyself-administer one or more doses of the drug per day by subcutaneousinjection. Insulin is a polypeptide with a nominal molecular weight of6,000 Daltons. Insulin has traditionally been produced by processing pigand cow pancreas to allow isolation of the natural product. Morerecently, recombinant technology has made it possible to produce humaninsulin in vitro. It is the currently common practice in the UnitedStates to institute the use of recombinant human insulin in all of thosepatients beginning insulin therapy.

[0004] It is known that most proteins are rapidly degraded in the acidicenvironment of the GI tract. Since insulin is a protein which is readilydegraded in the GI tract, those in need of the administration of insulinadminister the drug by subcutaneous injection (SC). No satisfactorymethod of orally administering insulin has been developed. The lack ofsuch an oral delivery formulation for insulin creates a problem in thatthe administration of drugs by injection can be both psychologically andphysically painful.

[0005] In an effort to provide for a non-invasive means foradministering insulin, and thereby eliminate the need for hypodermicsyringes, aerosolized insulin formulations have been tested. Aerosolizedinsulin formulations have been shown to produce insulin blood levels inman when these aerosols are introduced onto nasal or pulmonary membrane.Moses et al. [Diabetes, Vol. 32, November 1983] demonstrated that ahypoglycemic response could be produced following nasal administrationof 0.5 units/kg. Significant inter-subject variability was noted, andthe nasal insulin formulation included unconjugated bile salts topromote nasal membrane penetration of the drug. Salzman et al. [NewEngland Journal of Medicine, Vol. 312, No. 17] demonstrated that anintranasal aerosolized insulin formulation containing a non-ionicdetergent membrane penetration enhancer was effective in producing ahypoglycemic response in diabetic volunteers. Their work demonstratedthat nasal irritation was present in varying degrees among the patientsstudied. In that diabetes is a chronic disease which must becontinuously treated by the administration of insulin and in thatmucosal irritation tends to increase with repeated exposures to themembrane penetration enhancers, efforts at developing a non-invasivemeans of administering insulin via nasal administration have not beencommercialized.

[0006] In 1971, Wigley et al. [Diabetes, Vol 20, No. 8] demonstratedthat a hypoglycemic response could be observed in patients inhaling anaqueous formulation of insulin into the lung. Radio-immuno assaytechniques demonstrated that approximately 10 percent of the inhaledinsulin was recovered in the blood of the subjects. Because the surfacearea of membranes available to absorb insulin is much greater in thelung than in the nose, no membrane penetration enhancers are requiredfor delivery of insulin to the lungs by inhalation. The inefficiency ofdelivery seen by Wigley was greatly improved in 1979 by Yoshida et al.[Journal of Pharmaceutical Sciences, Vol. 68, No. 5] who showed thatalmost 40 percent of insulin delivered directly into the trachea ofrabbits was absorbed into the bloodstream via the respiratory tract.Both Wigley and Yoshida showed that insulin delivered by inhalationcould be seen in the bloodstream for two or more hours followinginhalation.

[0007] Aerosolized insulin therefore can be effectively given if theaerosol is appropriately delivered into the lung. In a review article,Dieter Kohler [Lung, supplement pp. 677-684] remarked in 1990 thatmultiple studies have shown that aerosolized insulin can be deliveredinto and absorbed from the lung with an expected absorption half-life of15-25 minutes. However, he comments that “the poor reproducibility ofthe inhaled dose [of insulin] was always the reason for terminatingthese experiments.” This is an important point in that the lack ofprecise reproducibility with respect to the administration of insulin iscritical. The problems associated with the inefficient administration ofinsulin cannot be compensated for by administering excess amounts of thedrug in that the accidental administration of too much insulin could befatal.

[0008] Effective use of an appropriate nebulizer can achieve highefficiency in delivering insulin to human subjects. Laube et al.[Journal of Aerosol Medicine, Vol. 4, No. 3, 1991 ] have shown thataerosolized insulin delivered from a jet nebulizer with a mass medianaerodynamic diameter of 1.12 microns, inhaled via a holding chamber at aslow inspiratory flow rate of 17 liters/minute, produced an effectivehypoglycemic response in test subjects at a dose of 0.2 units/kg.Colthorpe et al. [Pharmaceutical Research, Vol. 9, No. 6, 1992] haveshown that aerosolized insulin given peripherally into the lung ofrabbits produces a blood concentration versus time profile of over 50percent in contrast to 5.6 percent blood concentration versus timeprofile seen for liquid insulin dripped onto the central airways.Colthorpe's work supports the contention that aerosolized insulin mustbe delivered peripherally into the lung for maximum efficiency and thatinadvertent central deposition of inhaled aerosolized insulin willproduce an effect ten times lower than that desired. Variations indosing of 10-fold are clearly unacceptable with respect to theadministration of most drugs, and in particular, with respect to theadministration of insulin.

[0009] The present invention endeavors to provide a non-invasivemethodology for enhancing treatment of diabetic patients via aerosolizeddelivery.

SUMMARY OF THE INVENTION

[0010] Aerosolized delivery of insulin is disclosed wherein the insulinis monomeric insulin. Aerosolized delivery of monomeric insulin issignificantly less affected by an inhaling patient's breathing patternas compared to the effect on conventional recombinant insulin. Morespecifically, the maximum insulin concentration (C_(MAX)) and the timeneeded to obtain the maximum concentration (T_(MAX)) are much lessaffected by the amount of air inhaled after delivery of aerosolizeddrug. Accordingly, a higher degree of repeatability of dosing can beobtained (with monomeric insulin as compared to regular insulin) makingit substantially more practical for patients to control glucose levelsby inhaling insulin-thereby making diabetics less dependent on injectinginsulin.

[0011] When delivering aerosolized insulin the patient can be coached(by teaching and/or by the device which measures flow rate and/orvolume) to inhale at a given rate and to inhale a given amount of air(before and after the aerosol is released). One of the findingsdisclosed here is that the inhaled volume at delivery does notsubstantially affect the blood concentration versus time profile for theaerosolized delivery of monomeric insulin. However, the inhaled volumeat delivery does substantially affect the blood concentration versustime profile of regular insulin. Accordingly, one aspect of theinvention is the aerosolized delivery of monomeric insulin withoutregard to respiratory maneuver parameters such as inhaled volume. Asecond aspect of the invention is aerosolized delivery of insulin whichis not monomeric insulin while measuring inhaled volume and insuringthat the inhaled volume is (1) repeated for each dose in the same amountand (2) preferably a large inhaled volume, e.g. 80% or more of the lungcapacity of the patient. It should be noted that to obtain the mostrepeatable results that monomeric insulin should be delivered each timeat substantially the same inspiratory flow rate and inspiratory volumeat delivery and such delivery should be followed by the same inhaledvolume which is preferably a maximum inhaled volume.

[0012] The monomeric insulin formulation may be in any form, e.g., a drypowder, or dispersed or dissolved in a low boiling point propellant.However, the formulation is more preferably an aqueous solution having apH close to 7.4±1.0 which can be aerosolized into particles having aparticle diameter in the range of about 1.0 to about 4.0 microns.Formulations of monomeric insulin are preferably aerosolized andadministered via hand-held, self-contained devices which areautomatically actuated at the same release point in a patient'sinspiratory flow cycle. The release point is automatically determinedeither mechanically or, more preferably calculated by a microprocessorwhich receives data from a sensor making it possible to determineinspiratory flow rate and inspiratory volume. The device can measureparameters including inspiratory flow rates and volumes and provideinformation to the patient which can aid in controlling the patient'srespiratory maneuvers. Preferably the device is loaded with a cassettecomprised of an outer housing which holds a package of individualdisposable collapsible containers of a monomeric insulin analogcontaining formulation for systemic delivery. Actuation of the deviceforces the monomeric insulin formulation through a porous membrane ofthe container which membrane has pores having a diameter in the range ofabout 0.25 to 3.0 microns, preferably 0.25 to 1.5 microns. The porousmembrane is positioned in alignment with a surface of a channel throughwhich a patient inhales air.

[0013] The dose of insulin analog to be delivered to the patient varieswith a number of factors—most importantly the patient's blood glucoselevel. Thus, the device can deliver all or any proportional amount ofthe formulation present in the container. If only part of the contentsare aerosolized the remainder may be discarded. By delivering anyproportional amount of a container the patient can adjust the dose toany desired level while using containers which all contain the sameamount of monomeric insulin.

[0014] Smaller particle sizes are preferred to obtain systemic deliveryof insulin analog. Thus, in one embodiment, after the aerosolized mistis released into the channel the air surrounding the particles may beheated in an amount sufficient to evaporate carrier and thereby reduceparticle size. The air drawn into the device can be actively heated bymoving the air through a heating element which element is pre-heatedprior to the beginning of a patient's inhalation. The amount of energyadded can be adjusted depending on factors such as the desired particlesize, the amount of the carrier to be evaporated, the water vaporcontent of the surrounding air and the composition of the carrier (seeU.S. Pat. 5,522,385 issued Jun. 4, 1996).

[0015] To obtain systemic delivery it is desirable to get theaerosolized formulation deeply into the lung. This is obtained, in part,by adjusting particle sizes. Particle diameter size is generally aboutone to three times the diameter of the pore from which the particle isextruded. In that it is technically difficult to make pores of 1.0micron or less in diameter the use of evaporation can reduce particlesize to 3.0 microns or less even with pore sizes well above 1 micron.Energy may be added in an amount sufficient to evaporate all orsubstantially all carrier and thereby provide particles of dry powderedinsulin or highly concentrated insulin formulation to a patient whichparticles are uniform in size regardless of the surrounding humidity andsmaller due to the evaporation of the carrier.

[0016] In addition to adjusting particle size, systemic delivery ofinsulin is obtained by releasing an aerosolized dose at a desired pointin a patient's respiratory cycle. When providing systemic delivery it isimportant that the delivery be reproducible.

[0017] Reproducible dosing of insulin to the patient is obtained by: (1)using monomeric insulin which has been shown here to be less affected bythe patient's respiratory pattern, and/or; (2)providing for automaticrelease of formulation in response to a determined inspiratory flow rateand measured inspiratory volume. The automatic release method involvesmeasuring for, determining and/or calculating a firing point or drugrelease decision based on instantaneously (or real time) calculated,measured and/or determined inspiratory flow rate and inspiratory volumepoints. To obtain repeatability in dosing, the formulation is repeatedlyreleased at the same measured (1) inspiratory flow rate and (2)inspiratory volume. To maximize the efficiency of delivery aerosols arereleased at (3) a measured inspiratory flow rate in the range of fromabout 0.1 to about 2.0 liters/second and (2) a measured inspiratoryvolume in the range of about 0.1 to about 1.5 liters. After the aerosolis released the patient preferably continues inhaling to a maximuminhalation point.

[0018] A primary object of the invention is to provide for a method ofincreasing the repeatability at which glucose levels can be controlledby aerosol delivery of monomeric insulin.

[0019] An advantage of the invention is that the aerosolized delivery ofmonomeric insulin is substantially less affected by a patient'sbreathing maneuvers during delivery as compared to regular insulin andspecifically is less affected by how much the patient inhales afteraerosolized delivery.

[0020] A feature of the invention is the commercially available insulinlispro can be used in the method.

[0021] Another object is to provide a method of administering amonomeric insulin analog formulation to a patient wherein theformulation is repeatedly delivered to a patient at the same measuredinspiratory flow rate (in the range of 0.1 to 2.0 liters/second) andseparately determined inspiratory volume (beginning delivery in therange of 0.15 to 1.5 liters and continuing inspiration to maximum, e.g.,4-5 liters).

[0022] Another object of the invention is to combine delivery therapiesfor inhaling monomeric insulin with monitoring technologies so as tomaintain tight control over the serum glucose level of a patientsuffering from diabetes mellitus.

[0023] Another object of the invention is to provide a device whichallows for the intrapulmonary delivery of controlled amounts ofmonomeric insulin formulation based on the particular needs of thediabetic patient including serum glucose levels and insulin sensitivity.

[0024] Another object of the invention is to provide a means fortreating diabetes mellitus which involves supplementing monomericinsulin administration using an intrapulmonary delivery means incombination with injections of insulin and/or oral hypoglycemic agentssuch as sulfonylureas.

[0025] Another advantage of the present invention is that themethodology allows the administration of a range of different size dosesof monomeric insulin by a convenient and painless route, thus decreasingthe probability of insulin overdosing and increasing the probability ofsafely maintaining desired serum glucose levels.

[0026] Another feature of the device of the present invention is that itmay be programmed to provide variable dosing (from the same sizecontainer) so that different doses are delivered to the patient atdifferent times of the day coordinated with meals and/or other factorsimportant to maintain proper serum glucose levels with the particularpatient. Another feature of the invention is that the portable,hand-held inhalation device of the invention can be used in combinationwith a portable device for measuring serum glucose levels in order toclosely monitor and titrate dosing based on actual glucose levels.

[0027] Yet another feature of the invention is that the microprocessorof the delivery device can be programmed to prevent overdosing bypreventing formulation release more than a given number of times withina given period of time.

[0028] Another object of the invention is to adjust particle size byheating air surrounding the particles in an amount sufficient toevaporate carrier and reduce total particle size.

[0029] Another object is to provide a drug delivery device whichincludes a desiccator for drying air in a manner so as to remove watervapor and thereby provide consistent particle sizes even when thesurrounding humidity varies.

[0030] Another object is to provide a device for the delivery ofaerosols which measures humidity via a solid state hygrometer.

[0031] A feature of the invention is that drug can be dispersed ordissolved in a liquid carrier such as water and dispersed to a patientas dry or substantially dry particles of monomeric insulin.

[0032] Another advantage is that the size of the particles deliveredwill be relatively independent of the surrounding humidity.

[0033] It is an object of this invention to demonstrate a novelapplication for Humalog™ as a monomeric insulin analog well suited forpulmonary drug delivery.

[0034] It is an object of this invention to demonstrate that Humalog™provides unique benefits when delivered via the lung by reducing thedegree to which lung sequestration occurs following aerosolizeddelivery.

[0035] It is an object of this invention to demonstrate that aerosolizeddelivery of Humalog™ in place of conventional formulations ofrecombinant human insulin makes a repeatable blood concentration versustime profile substantially less dependent on the patients final inhaledvolume at delivery.

[0036] It is an object of this invention to demonstrate that byincreasing the blood concentration versus time profile of the deliveredmonomeric insulin such as Humalog™ (regardless of breathing maneuverafter delivery) that a more reproducible and consistent effect on serumblood glucose can be achieved.

[0037] It is another object of this invention to demonstrate that theincreased reproducibility seen after the delivery of Humalog™ viaaerosolization into the lung results in a more economical approach tothe pulmonary drug delivery of insulin than offered by the delivery ofregular recombinant human insulin to the lung via aerosolization.

[0038] These and other objects, advantages and features of the presentinvention will become apparent to those persons skilled in the art uponreading the details of the structure of the device, formulation ofcompositions and methods of use, as more fully set forth below.

BRIEF DESCRIPTION OF THE FIGS.

[0039]FIG. 1 is a graph plotting the change in serum insulin levels overtime following different methods of insulin administration;

[0040]FIG. 2 is a graph plotting the change in immunoreactive insulin inblood serum over time following different methods of insulin lisproadministration.

[0041]FIG. 3 is a graph showing V_(L) and V_(H) in a preferred breathingpattern at delivery.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0042] Before the present method of delivering aerosolized monomericinsulin to treat diabetes mellitus and devices, containers andformulations used in the treatment are described, it is to be understoodthat this invention is not limited to the particular methodology,containers, devices and formulations described, as such methods, devicesand formulations may, of course, vary. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of the presentinvention which will be limited only by the appended claims.

[0043] It must be noted that as used herein and in the appended claims,the singular forms “a,” “and,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a formulation” includes mixtures of different formulations, referenceto “an analog” refers to one or mixtures of insulin analogs, andreference to “the method of treatment” includes reference to equivalentsteps and methods known to those skilled in the art, and so forth.

[0044] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methods,devices and materials similar or equivalent to those described hereincan be used in the practice or testing of the invention, the preferredmethods, devices and materials are now described. All publicationsmentioned herein are incorporated herein by reference for the purpose ofdescribing and disclosing devices, formulations and methodologies whichare described in the publication and which might be used in connectionwith the presently described invention.

[0045] Publications cited herein are cited for their disclosure prior tothe filing date of the present application. Nothing here is to beconstrued as an admission that the inventors are not entitled toantedate the publications by virtue of an earlier priority date or priordate of invention. Further the actual publication dates may be differentfrom those shown and require independent verification.

DEFINITIONS

[0046] The term “insulin” shall be interpreted to encompass fast acting“regular” insulin, natural extracted human insulin, recombinantlyproduced human insulin, insulin extracted from bovine and/or porcinesources, recombinantly produced porcine and bovine insulin and mixturesof any of these insulin products. The term is intended to encompass thepolypeptide normally used in the treatment of diabetics in asubstantially purified form but encompasses the use of the term in itscommercially available pharmaceutical form which includes additionalexcipients. Regular insulin is preferably recombinantly produced and maybe dehydrated (completely dried) or in solution. For purposes of thepresent invention insulin is particularly characterized by moleculeswhich form complexes, particularly hexamers in solution and when in thehuman body the hexamer complexes disassociate much more slowly thanmonomeric insulin.

[0047] The “monomeric insulin” is intended to encompass any form of aninsulin molecule which is different from regular insulin wherein thedifference results in the insulin molecules not maintaining hexamercomplexes in a human which hexamers are characteristic of insulin.Monomeric insulin exists predominantly in a monomer form or quicklydissociates into a monomeric form in the human body. The change whichinduces the monomeric form may be caused by one or more of the aminoacids within the polypeptide chain being replaced with an alternativeamino acid and/or wherein one or more of the amino acids has beendeleted or wherein one or more additional amino acids has been added tothe polypeptide chain or amino acid sequences which act as insulin indecreasing blood glucose levels and/or where bonds such as disulfidebonds are deleted, added or moved in position relative to natural humaninsulin. The change may also by obtained by using a different salt forme.g. replacing the zinc cations with sodium cations. The preferredmonomeric insulin is insulin lispro in a zinc salt form as disclosed inU.S. Pat. No. 5,547,929, issued Aug. 20, 1996 and see also U.S. Pat.Nos. 5,514,646 and 5,700,662 all of which are incorporated herein byreference. It should be noted that insulin as well as monomeric insulinwill disassociate into monomeric forms over time. However, monomericinsulin will disassociate into the monomeric form, in a human body, attwice the rate or faster than insulin when it is administeredsubcutaneously. It should be noted that insulin lispro disassociatesinto the monomeric form at approximately three times the rate ascompared to regular insulin when it is administered subcutaneously.

[0048] The terms “V_(H)” and “high volume” are used interchangeably hereand shall mean that after an aerosolized dose is created the patientinhales the dose and continues to inhale a high volume. Morespecifically, the patient inhales a high volume which is approximately80% or more of the patient's total lung capacity. For an adult with a 5liter lung volume the inhalation would be approximately 4 liters or morei.e. up to the total lung volume. Some error should be accounted for.Thus the high volume can be 65% to 100% of the total lung volumedepending on the lung volume of the patient. Within the specificexamples shown here the high inhaled volume for healthy male patientswith a total lung volume of approximately 5 liters was in general about4.7 liters. High volume is preferably as close to 100% as the patientcan inhale.

[0049] The terms “V_(L)” and “Low volume” refer to a smaller inhaledvolume as compared to an inhaled high volume of air with the aerosolizeddelivery of insulin. Even without inhaling the lung will retain someair. Thus, a low inhaled volume is approximately 40% plus or minus 15%of the patient's total lung volume. For the experiments shown here a lowinhaled volume involved inhaling approximately 3 liters or less. Itshould be noted that inhaled volumes are volumes recorded at BodyTemperature and Pressure Standard, i.e. the units are liters (btps). Theterms V_(L) V_(H) can be further understood in connection with FIGS. 3and it description.

[0050] The term “acceptable serum glucose level” is intended to mean aglucose level above 50 mg/dl and below 300 mg/dl, more preferably 80mg/dl to 200 mg/dl and most preferably about 100 mg/dl. It will beunderstood by those skilled in the art that levels of about 50 mg/dl areconsidered low and that levels of about 300 mg/dl are considered high,although acceptable in the sense that these levels are generally notfatal. It is an important aspect of the invention to maintain moreacceptable levels which are above the low of 50 mg/dl and below the highof 300 mg/dl with it being more acceptable to deliver doses of insulinso as to keep the patient as close as possible to about 100 mg/dl.

[0051] The term “blood concentration versus time profile” shall beinterpreted to mean the concentration of a drug in the blood or plasmaover time. This can be characterized by means of a graph showing theconcentration of a drug (e.g. insulin or an insulin analog or“immunoreactive insulin” as a surrogate measurement for an insulinanalog such as insulin lispro) on the Y axis and time on the X axis. Theblood concentration versus time profile can also be characterized bycertain pharmacokinetic parameters such as C_(max) (the maximumconcentration of the drug seen over the measured time interval) andT_(max) (the time at which C_(max) was observed). Note that, by thesecriteria, two different blood concentration versus time profiles may beassociated with similar or even identical bioavailability measurements.The blood concentration versus time profile is crucial for drugs such asinsulin and insulin analogs where the time at which peak concentrationpreferably occurs in conjunction with peak blood glucose levelsfollowing a meal. Different values of T_(max) for two different insulinpreparations or delivery methods could therefore be associated withsignificant differences in safety and efficacy.

[0052] The term “dosing event” shall be interpreted to mean theadministration of regular insulin and/or monomeric insulin to a patientin need thereof by the intrapulmonary route of administration whichevent may encompass one or more releases of formulation from adispensing device (from one or more containers) over a period of time of15 minutes or less, preferably 10 minutes or less, and more preferably 5minutes or less, during which period one or more inhalations are made bythe patient and one or more doses of regular insulin or monomericinsulin are released and inhaled. A dosing event shall involve theadministration of regular insulin or monomeric insulin to the patient inan amount of about 1 unit to about 30 units in a single dosing eventwhich may involve the release of from about 1 to about 300 units fromthe device.

[0053] The term “inspiratory flow rate” shall mean a value of air flowrate measured, calculated and/or determined based on the speed of theair passing a given point in a measuring device assuming atmosphericpressure ±5% and a temperature in the range of about 10° C. to 40° C.

[0054] The term “inspiratory flow” shall be interpreted to mean a valueof air flow calculated based on the speed of the air passing a givenpoint along with the volume of the air that has passed that point withthe volume calculation being based on integration of the flow rate dataand assuming atmospheric pressure, ±5% and temperature in the range ofabout 10° C. to about 40° C.

[0055] The term “inspiratory volume” shall mean a determined, calculatedand/or measured volume of air passing a given point into the lungs of apatient assuming atmospheric pressure ±5% and a temperature in the rangeof 10° C. to 40° C.

[0056] The term “inhaling maximally” shall mean that the patient makes amaximal effort to inhale air into the lungs.

[0057] The term “inspiratory flow profile” shall be interpreted to meandata calculated in one or more events measuring inspiratory flow andcumulative volume, which profile can be used to determine a point withina patient's inspiratory cycle which is preferred for the release ofaerosol to be delivered to a patient. The point within the inspiratorycycle where drug is released may be based on a point within theinspiratory cycle likely to result in the maximum delivery of drugand/or based on a point in the cycle most likely to result in thedelivery of a reproducible amount of drug to the patient at each releaseof drug. Repeatability of the amount delivered is the primary criterionand maximizing the amount delivered is an important but secondarycriterion. Thus, a large number of different drug release points mightbe selected and provide for repeatability in dosing provided theselected point is again selected for subsequent releases. To insuremaximum drug delivery the point is selected within given parameters.

[0058] The term “therapeutic index” refers to the therapeutic index of adrug defined as the ratio of toxic to therapeutic dose. Drugs with atherapeutic index near unity achieve their therapeutic effect at dosesvery close to the toxic level and as such have a narrow therapeuticwindow, i.e. a narrow dose range over which they may be administered.

[0059] The term “liquid formulation” is used herein to describe anypharmaceutically active insulin, including insulin and/or monomericinsulin for treating diabetes mellitus by itself or with apharmaceutically acceptable carrier in flowable liquid form andpreferably having a viscosity and other characteristics such that theformulation is aerosolized into particles which are inhaled into thelungs of a patient after the formulation is moved through a porousmembrane of the invention. Such formulations are preferably solutions,e.g. aqueous solutions, ethanolic solutions, aqueous/ethanolicsolutions, saline solutions and colloidal suspensions. Formulations canbe solutions or suspensions of drug in any fluid including fluids in theform of a low boiling point propellant.

[0060] The term “formulation” is used to encompass the term “liquidformulation” and to further include dry powders of insulin and/ormonomeric insulin along with excipient materials. Preferred formulationsare aqueous solutions of monomeric insulin but include dry powders anddispersions.

[0061] The term “substantially” dry shall mean particles of an aerosolwhich contain less than 10% free water, ethanol or other liquid carrierbased on total weight and preferably contains no detectable free liquidcarrier.

[0062] The term “bulk flow rate” shall mean the average velocity atwhich air moves through a channel considering that the flow rate is at amaximum in the center of the channel and at a minimum at the innersurface of the channel.

[0063] The term “flow boundary layer” shall mean a set of pointsdefining a layer above the inner surface of a channel through which airflows wherein the air flow rate below the boundary layer issubstantially below the bulk flow rate, e.g., 50% or less than the bulkflow rate.

[0064] The term “carrier” shall mean a non-active portion of aformulation. In aqueous formulations, it is a liquid, flowable,pharmaceutically acceptable excipient material which insulin and/ormonomeric insulin is suspended in or more preferably dissolved in. In adry powder, it shall include non-active components, e.g., to keep theparticles separate. Useful carriers do not adversely interact with themonomeric insulin and have properties which allow for the formation ofaerosolized particles—preferably particles having a diameter in therange of 0.5 to 3.0 microns when a formulation comprising the carrierand insulin analog is forced through pores having a diameter of 0.25 to3.0 microns. Preferred carriers for liquid solutions include water,ethanol and mixtures thereof. Other carriers can be used provided thatthey can be formulated to create a suitable aerosol and do not adverselyaffect insulin, monomeric insulin or human lung tissue.

[0065] The term “measuring” describes an event whereby either theinspiratory flow rate or inspiratory volume of the patient is measured(via electronic sensors or by mechanical means) in order to determine anoptimal point in the inspiratory cycle at which to release aerosolizeddrug. An actual measurement of both rate and volume may be made or therate can be directly measured and the volume calculated based on themeasured rate. It is also preferable to continue measuring inspiratoryflow during and after any drug delivery and to record inspiratory flowrate and volume before, during and after the release of drug. Suchreading makes it possible to determine if drug was properly delivered tothe patient.

[0066] Each of the parameters discussed above is measured duringquantitative spirometry. A patient's individual performance can becompared against his personal best data, individual indices can becompared with each other for an individual patient (e.g. FEV₁ divided byFVC, producing a dimensionless index useful in assessing the severity ofacute asthma symptoms), or each of these indices can be compared againstan expected value. Expected values for indices derived from quantitativespirometry are calculated as a function of the patient's sex, height,weight and age.

GENERAL METHODOLOGY

[0067] The invention comprises aerosolizing a formulation of monomericinsulin (e.g. insulin lispro) and inhaling the aerosolized formulationinto the lungs. Although the inhalation of insulin which results in theinsulin entering the circulatory system is known, correctly dosing theamount of insulin delivered by inhalation has been problematic—however,see U.S. Pat. No. 5, 672,581 issued Sep. 30, 1997. The devices,formulations and methods disclosed herein are useful in solving problemswith prior methods. For example, when regular insulin is delivered to apatient by inhalation the amount of effect on glucose levels variesconsiderably based on the lung volume inhaled by the patient with theaerosolized insulin at delivery. If the blood glucose level is notquickly lowered the patient may administer additional insulin which incombination with that already administered will dangerously lower theblood glucose level. The present invention endeavors to provide apreferred blood concentration versus time profile by the delivery ofmonomeric insulin which rapidly disassociates into its monomeric form ina human and as such moves into the circulatory system more rapidly ascompared to regular insulin. When regular insulin is delivered byinhalation, the effect on lowering glucose levels is often differentdepending on the total inhaled volume of by the patient at delivery.Results provided here show that the delivery of monomeric insulin ismuch less effected by the patient's total inhaled volume at deliveringas compared to the aerosolized delivery of regular insulin therebyimproving repeatability of dosing. Thus, the data shown here provideimproved unexpected results with respect to a practical method oftreating Diabetes Mellitus by aerosolized drug delivery.

[0068]FIGS. 1 and 2 along with tables 1 and 2 dramatically show how thetotal inhaled volume at delivery has a dramatically greater effect onthe blood concentration versus time profile following aerosolizeddelivery of insulin as compared to aerosolized delivery of monomericinsulin. In tables 1 and 2 as well as within FIGS. 1 and 2 a referenceis made to “V_(L)” and “V_(H)” which refers to low volume and highvolume inhalations at delivery respectively. A more completeunderstanding of what is meant by these terms and how the invention iscarried out can be understood by reference to FIG. 3.

[0069]FIG. 3 is a graph of inspiratory volume verses inspiratory flowrate in liters per second. Regardless of whether one is deliveringinsulin or monomeric insulin it is preferable to begin the release ofthe aerosolized dose to the patient when the inhaled inspiratory volumeand inspiratory flow rate are within the parameters of the rectangle 1shown in FIG. 3. In the specific example of FIG. 3 the release occurs atthe point 2. The parameters of the rectangle shown indicate that releaseshould occur at an inspiratory volume above 0.1 liter and prior to 0.8liter. Further, the aerosol is released after the patients inhalationrate exceeds 0.1 liters per second but prior to the rate exceeding the2.0 liters per second. In the examples shown the release occurs at aninspiratory volume of about 0.5 liters and at an inspiratory rate ofabout 1.0 liters per second. To enhance repeatability of dosing thepatient would deliver each dose of insulin thereafter at the sameinspiratory volume and inspiratory flow rate. More specifically thedevice of the invention will automatically release the aerosolized doseafter it records an inspiratory volume of about 0.5 liters and aninspiratory flow rate of about 1 liter per second. Thereafter, thepatient is coached to continue inhalation at the same rate e.g. at arate of about 1 liter per second. For a low volume maneuver theinhalation is continued until the patient has inhaled 2 liters of air asshown by the point 3 in FIG. 3. For a high volume maneuver the patientcontinues inhaling until the patient has inhaled 4 liters of air or moreas shown by point 4 in FIG. 3.

[0070] A comparison of FIGS. 1 and 2 as well as tables 1 and 2 showsthat inhaling to a low or high volume at delivery does not effect theresults significantly results when delivering monomeric insulin—butsubstantially effects results when delivering insulin.

[0071] The preferred monomeric insulin is insulin lispro as described inthe 1997 PDR at page 1488 (incorporated herein by reference). Thispreferred monomeric insulin is also referred to herein by the commercialname “Humalog™.” The following provides a description of the conceptualbasis of the present invention.

[0072] Insulin has been used for over 50 years for the management ofdiabetes mellitus. Insulin is a naturally occurring hormone which playsa clinical role in glucose metabolism and its absence in patients withType I Diabetes is a fatal illness unless exogenous insulin is used aspart of an insulin replacement therapy program.

[0073] Patients have self administered insulin subcutaneously (SC) fordecades as a means for managing their diabetes. The total daily dose ofinsulin required by individual patients varies. The availability ofportable blood glucose monitors over the last decade has been asignificant advancement in that patients can now measure their own bloodglucose levels in self dose insulin by injection according to theirneeds. Many things affect the daily requirement for insulin. Thesemultiple factors require that patients measure blood glucose levels toachieve tight control of their blood glucose.

[0074] The Diabetes Complications and Control Trial (DCCT), amulticenter study designed to evaluate the potential long termbeneficial effects of tight blood glucose control, was recentlycompleted. This study demonstrated that insulin requiring diabetics whomaintained their serum glucose within a specific range over time had asignificantly reduced complication rate, including the avoidance of theconsequences of peripheral vascular disease (e.g. renal failure, chronicdiabetic retinopathy and lower extremity problems).

[0075] A key element in the attainment of a stable blood glucose levelover time involves the administration of subcutaneously administeredinsulin prior to mealtime. In this way, blood levels of insulin willappear coincident with the increase in blood glucose associated withmeal digestion. Recombinant human insulin, which has been available forover more than 10 years, is available in a short acting form (regularinsulin) which is appropriate for self administration by injection priorto meal time. Unfortunately, recombinant human insulin must be dosed byinjection approximately one half hour prior to meal time in order toinsure that a rise in blood glucose does not occur unopposed byexogenous insulin levels.

[0076] The requirement that recombinant human insulin be injected onehalf hour prior to meal time is burdensome because it requires thatpatients precisely anticipate the times they will be eating. Eli Lillyhas recently introduced insulin lispro which is sold as Humalog™ (arecombinant human insulin analog), which is more rapidly absorbed thanrecombinant human insulin when injected subcutaneously. Because it worksmore quickly than recombinant human insulin, Humalog™ can be given justprior to mealtime thereby reducing the burden on the patient to planahead prior to eating.

[0077] Recombinant human insulin in aqueous solution is in a hexamericconfiguration.

[0078] In other words, six molecules of recombinant insulin arenoncovalently associated in a hexameric complex when dissolved in waterin the presence of zinc ions. Studies have demonstrated that hexamericinsulin is not rapidly absorbed from the subcutaneous space. In orderfor recombinant human insulin to be absorbed into circulation, thehexameric form must first dissociate into dimer and/or a monomeric formsi.e., these forms are required before the material can transit into theblood stream. This requirement for recombinant human insulin todisassociate from hexameric to dimer or monomeric form prior toabsorption is believed to be responsible for the 30 minutes required fora self administered dose of subcutaneous recombinant human insulin toproduce a measurable therapeutic blood level.

[0079] Although Humalog™ exists in solution outside the body as ahexamer, it very rapidly disassociates into a monomeric form followingsubcutaneous administration. Clinical studies have demonstrated thatHumalog™ is absorbed quantitatively faster than recombinant humaninsulin after subcutaneous administration.

[0080] To control glucose levels insulin is dosed in units. Becauseinsulin is generally in the form of regular insulin and is generallyadministered subcutaneously the units of measurements used here aresubcutaneous equivalents of regular insulin.

[0081] Because insulin must be administered frequently in order to allowpatients to attain a tight degree of control over their serum glucose,the fact that all insulin products currently need to be delivered byinjection is a hindrance to compliance. Results from a DCCT studydemonstrate that insulin should ideally be administered 4-6 times eachday in order for patients to be likely to achieve an adequate level ofblood glucose control to obtain a reduction in complication rateassociated with diabetes. A noninvasive method for the delivery ofinsulin could be beneficial in increasing patient compliance withfrequent self administration of insulin throughout the day.

[0082] The noninvasive delivery of proteins and peptides has been anelusive goal of the drug delivery industry. Because proteins are rapidlydisassociated in the GI tract, oral forms for the delivery of proteinsas tablets or capsules have thus far seen limited success. Inhalationaldrug delivery has been demonstrated to be a viable option for thedelivery of proteins and peptides such as insulin via the lung, see U.S.Pat. No. 5,364,838, issued Nov. 15, 1994 and 5,672,581 issued Sep. 30,1997.

[0083] Recent studies have demonstrated that insulin can be reproduciblyadministered for inhalation to healthy volunteers producing a rapid risein measurable serum glucose level as well as a rapid fall in bloodglucose. U.S. Pat. No. 5,544,646 describes systems for theintrapulmonary delivery of aerosolized aqueous formulations. The systemdescribed allows unit dosed packages of aqueous formulated drug to bedelivered deep into the lung for systemic effect. U.S. Pat. No.5,558,085, Intrapulmonary Delivery of Peptide Drugs illustrates howproteins and peptides can be delivered as fine particle aerosols throughthe lung for systemic effect. U.S. Pat. No. 5,497,763 describes adisposable package for intrapulmonary delivery of aerosolizedformulations which allows sealed packets of preformulated drugs such asinsulin to be inserted by the patient into aerosolization apparatus forproducing fine particle aerosols for deep inhalation.

[0084] By quantitatively measuring the inspiratory flow rate and volumeduring the patients_inspiratory maneuver while breathing through theaerosolization system, an optimum point for the delivery of a bolus ofaerosolized medication can be determined. U.S. Pat. No. 5,509,404describes intrapulmonary drug delivery within therapeutically relevantinspiratory flow volume values and illustrates how specific inspiratoryflow rate and flow volume criteria can be used to enhance thereproducibility of drugs delivered via the lung for systemic effect.U.S. Pat. No. 5,522,385, Dynamic Particle Size Control for AerosolizedDrug Delivery demonstrates that the parameters of the emitted aerosolcan be varied to optimize the delivery of an inhaled aerosol forsystemic effect.

[0085] U.S. patent application Ser. No. 08/754,423, filed Nov. 11, 1996,illustrates that recombinant human insulin, when delivered as an aerosolfor deep inhalation into the lung for systemic effect, is sequestered inthe lung to a significant degree. This U.S. patent application describeshow insulin sequestered within the lung can be made to transit into thesystemic circulation if the patient engages in certain specificinspiratory maneuvers following delivery.

[0086] Although the reasons for sequestration of insulin in the lungfollowing aerosolized delivery are not known, we speculate that, as withsubcutaneous delivery, the dissociation of insulin from hexameric tomonomeric form is an important first step prior to the absorption ofinsulin into the blood stream. Recent controlled experiments conductedby the inventors quantified the degree to which insulin is sequesteredinto the lung following aerosolized delivery. In these controlledexperiments, the amount of insulin or monomeric insulin released intothe blood stream following aerosol delivery was quantified in cross overfashion with and then without a forced expiratory maneuver followingdelivery. Results shown here indicated that the blood concentrationversus time profile of monomeric insulin is not substantially affectedcompared to insulin by a patient's respiratory maneuver at delivery.

[0087] Although multiple studies have evaluated the feasibility of thedelivery of recombinant human insulin via the lung as a fine particleaerosol, no studies have appeared demonstrating that recombinant humaninsulin is sequestered in the lung following aerosolized delivery.Recently conducted clinical studies demonstrate that significantsequestration of recombinant human insulin is occurring in the lungfollowing aerosol drug delivery. Although this degree of sequestrationcan be reversed by certain specific pulmonary maneuvers as shown in ourcopending application, it will be desirable to substantially reduce oreliminate this sequestration altogether.

[0088] Because Humalog™ rapidly disassociates into monomeric insulin, itis uniquely suited for delivery via the lung.

[0089] The invention includes containers, devices and methods whichprovide a non-invasive means of treating diabetes mellitus in a mannerwhich makes it possible to accurately dose the administration ofaerosolized monomeric insulin and thereby maintain tight control overserum glucose levels of a patient suffering from the disease. The deviceof the invention provides a number of features which make it possible toachieve the controlled and repeatable dosing procedure required fortreating diabetes.

[0090] Specifically, the device is not directly actuated by the patientin the sense that no button is pushed nor valve released by the patientapplying physical pressure. On the contrary, the device of the inventionprovides that aerosolized insulin formulation is released automaticallyupon receipt of a signal from a microprocessor programmed to send asignal when data is received from a monitoring device such as an airflowrate monitoring device.

[0091] A patient using the device withdraws air from a mouthpiece andthe inspiratory rate of the patient is measured as is cumulativeinspiratory volume. The monitoring device continually sends informationto the microprocessor, and when the microprocessor determines that theoptimal point in the respiratory cycle is reached, the microprocessoractuates the opening of the valve allowing release of insulin.Accordingly, drug is always delivered at a pre-programmed place in therespiratory flow profile of the particular patient which is selectedspecifically to maximize reproducibility of drug delivery to theperipheral lung regions. It is pointed out that the device of thepresent invention can be used to, and actually does, improve theefficiency of drug delivery. However, this is not a critical feature.Important features are the enhanced repeatability of blood concentrationversus time profile and the increased rate at which insulin is broughtinto the circulatory system. The invention makes it possible to delivera tightly controlled amount of drug at a particular point in theinspiratory cycle so as to assure the delivery of a controlled andrepeatable amount of drug to the lungs of each individual patient.

[0092] The automatic control of monomeric insulin release provides arepeatable means controlling the glucose level of a patient. Becauseaerosolized monomeric insulin formulation is released automatically andnot manually, it can predictably and repeatedly be released in the sameamount each time to provide a preprogrammed measured amount which isdesired.

[0093] When it is desirable to decrease particle size by heating, aheating element is used. The amount of heat added to the air is about 20Joules or more, preferably 20 Joules to about 100 Joules and morepreferably 20 Joules to about 50 Joules per 10 μl of formulation.

[0094] There is considerable variability with respect to the amount ofinsulin which is delivered to a patient when the insulin is beingadministered by injection. Patients requiring the administration ofinjectable insulin use commercial insulin which is prepared inconcentrations of 100 units per milliliter, although higherconcentrations up to about 1,000 units per milliliter can be obtained.It is preferable to use more highly concentrated monomeric insulin inconnection with the present invention. If insulin containing 500 unitsof insulin per milliliter is used and a patient is administering 25units, then the patient will only need to administer 0.05 milliliters ofthe concentrated insulin to the lungs of the patient to achieve thedesired dose.

[0095] The symptoms of diabetes can be readily controlled with theadministration of insulin. However, it is extremely difficult, tonormalize the blood sugar throughout a 24-hour period utilizingtraditional insulin therapy given as one or two injections per day. Itis possible to more closely approach normalized blood sugar levels withthe present invention. Improvements are obtained by smaller, morefrequent dosing and by timing dosing relative to meals, exercise andsleep.

[0096] The precise amount of insulin administered to a patient variesconsiderably depending upon the degree of the disease and the size ofthe patient. A normal-weight adult may be started on about a 15-20 unitsa day (as explained above the units are equivalent subcutaneous units)in that the estimated daily insulin production rate in non-diabeticsubjects of normal size is approximately 25 units per day. It ispreferable to administer approximately the same quantity of insulin forseveral days before changing the dosing regime except with hypoglycemicpatients for which the dose should be immediately decreased unless aclearly evident nonrecurrent cause of hypoglycemia (such as not eating,i.e., missing a typical meal) is present. In general, the changes shouldnot be more than five to ten units per day. It is typical to administerabout two-thirds of the total insulin daily dosage before breakfast andadminister the remainder before supper. When the total dosage reaches 50or 60 units per day, a plurality of smaller doses are often requiredsince peak action of insulin appears to be dose related, i.e., a lowdose may exhibit maximal activity earlier and disappear sooner than alarge dose. All patients are generally instructed to reduce insulindosage by about 5 to 10 units per day when extra activity isanticipated. In a similar manner, a small amount of extra insulin may betaken before a meal that contains extra calories or food which is notgenerally eaten by the diabetic patient. The inhalation device of thepresent invention is particularly useful with respect to providing suchsmall amounts of additional insulin.

[0097] Several types of insulin formulations are commercially available.When larger doses of insulin must be administered at a single point intime, it may be preferable to administer intermediate or long-actinginsulin formulations. Such formulations release some insulin immediatelyand provide a more sustained release of the remainder of the insulinover time. Such formulations are described further below in the “InsulinContaining Formulations” section.

[0098] There is a differential between the amount of insulin and/ormonomeric insulin actually released from the device and the amountactually delivered to the patient. The present device is two to tentimes more efficient than conventional inhalation devices (i.e., MDIs ormetered dose inhalers) which have an efficiency as low as 10% meaningthat as little as 10% of the aerosolized insulin may actually reach thelungs of the patient. The efficiency of the delivery will vary somewhatfrom patient to patient and should be taken into account whenprogramming the device for the release of insulin. One of thedifficulties with aerosolized delivery of insulin is that the patientand/or the caregiver cannot determine precisely how much insulin hasentered the circulatory system. Accordingly, if the patient has beendosed with what is believed to be an adequate amount of aerosolizedinsulin and the glucose level remains high one might assume that theaerosolized dose was not properly delivered. For example, the insulinmight have been improperly delivered against the patient's mouthsurfaces or throat where it will not be absorbed into the circulatorysystem. However, it may be that the insulin is properly delivered to thelung (e.g., provided on the outer peripheral areas of the lung) but hasnot yet migrated into the circulatory system.

[0099] Obese patients are generally somewhat less sensitive to insulinand must be provided with higher doses of insulin in order to achievethe same effect as normal weight patients. Dosing characteristics basedon insulin sensitivity are known to those skilled in the art and aretaken into consideration with respect to the administration ofinjectable insulin. The present invention makes it possible to varydosing over time if insulin sensitivity changes and/or if usercompliance and/or lung efficiency changes over time.

[0100] Based on the above, it will be understood that the dosing oramount of monomeric insulin actually released from the device can bechanged based on the most immediately prior monitoring event wherein theinspiratory flow of a patient's inhalation is measured. The amount ofinsulin released can also be varied based on factors such as timing andtiming is, in general, connected to meal times, sleep times and, to acertain extent, exercise times. Although all or any of these events canbe used to change the amount of insulin released from the device andthus the amount of insulin delivered to the patient, ultimately, theamount released and delivered to the patient is based on the patient'sserum glucose levels. It is important to maintain the serum glucoselevels of the patient within acceptable levels (greater than 60 mg/dland less than 125 mg/100 ml, and most preferably to maintain thoselevels at about 80 mg/100 ml.

[0101] Variations in doses are calculated by monitoring serum glucoselevels in response to known amounts of insulin released from the device.If the response in decreasing serum glucose level is higher than withprevious readings, then the dosage is decreased. If the response indecreasing serum glucose level is lower than with previous readings,then the dosing amount is increased. The increases and decreases aregradual and are preferably based on averages (of 10 or more readings ofglucose levels after 10 or more dosing events) and not a single dosingevent and monitoring event with respect to serum glucose levels. Thepresent invention can record dosing events and serum glucose levels overtime, calculate averages and deduce preferred changes in administrationof insulin.

[0102] As another feature of the invention, the device can be programmedso as to prevent the administration of more than a given amount ofinsulin within a given period of time. For example, if the patientnormally requires 25 units per day of insulin, the microprocessor of theinhalation device can be programmed to prevent further release of thevalve after 35 units has been administered within a given day. Setting aslightly higher limit would allow for the patient to administeradditional insulin, if needed, due to larger than normal meals and/oraccount for misdelivery of insulin such as due to coughing or sneezingduring an attempted delivery.

[0103] The ability to prevent overdosing is a characteristic of thedevice due to the ability of the device to monitor the amount of insulinreleased and calculate the approximate amount of insulin delivered tothe patient based on monitoring given events such as airflow rate andserum glucose levels. The ability of the present device to preventoverdosing is not merely a monitoring system which prevents furthermanual actuation of a button. As indicated above, the device used inconnection with the present invention is not manually actuated, but isfired in response to an electrical signal received from amicroprocessor. Applicant's device does not allow for the release ofinsulin merely by the manual actuation of a button to fire a burst ofinsulin into the air.

[0104] The microprocessor of applicant's invention can be designed so asto allow for an override feature which would allow for theadministration of additional insulin. The override feature could beactuated in an emergency situation. Alternatively, the override featurecould be actuated when the device is electronically connected with aserum glucose level monitoring device which determines that serumglucose levels increase to dangerously high levels.

[0105] The microprocessor of applicant's invention will preferablyinclude a timing device. The timing device can be electrically connectedwith visual display signals as well as audio alarm signals. Using thetiming device, the microprocessor can be programmed so as to allow for avisual or audio signal to be sent when the patient would be normallyexpected to administer insulin. In addition to indicating the time ofadministration (preferably by audio signal), the device can indicate theamount of insulin which should be administered by providing a visualdisplay. For example, the audio alarm could sound alerting the patientthat insulin should be administered. At the same time, the visualdisplay could indicate “five units” as the amount of insulin to beadministered. At this point, a monitoring event could take place. Afterthe predetermined dose of five units had been administered, the visualdisplay would indicate that the dosing event had ended. If the patientdid not complete the dosing event by administering the stated amount ofinsulin, the patient would be reminded of such by the initiation ofanother audio signal, followed by a visual display instructing thepatient to continue administration.

[0106] Additional information regarding dosing with insulin viainjection can be found within Harrison's—Principles of Internal Medicine(most recent edition) published by McGraw Hill Book Company, New York,incorporated herein by reference to disclose conventional informationregarding dosing insulin via injection.

Treatment Via Monomeric Insulin

[0107] The methodologies of the present invention are preferably carriedout using recombinantly produced monomeric insulin in a liquidformulation. A preferred insulin is insulin lispro, sold by Lilly underthe name Humalog™. This analog is absorbed faster after subcutaneousinjection. Another type of insulin analog is referred to as superactiveinsulin. In general, superactive insulin has increased activity overnatural human insulin. Accordingly, such insulin can be administered insubstantially smaller amounts while obtaining substantially the sameeffect with respect to reducing serum glucose levels. Another generaltype of analog is referred to as hepatospecific insulin. Hepatospecificinsulin analogs are more active in the liver than in adipose tissue andoffer several advantages over currently available insulin therapy.Hepatospecific analogs provide preferential hepatic uptake duringperipheral subcutaneous administration, thereby mimicking, more closely,the metabolic balance between the liver and the peripheral tissues.Obtaining the correct metabolic balance is an important part of propertreatment of diabetics and administration via the intrapulmonary routeshould provide advantages over intermuscular injection with respect toobtaining such a balance. It may be desirable to include mixtures ofconventional insulin with insulin lispro or with insulin which ishepatospecific and/or with superactive insulin analogs. Hepatospecificanalogs are disclosed and described within published PCT applicationWO90/12814, published Nov. 1, 1990, which application is incorporatedherein by reference for its disclosure of such hepatospecific insulinanalogs and in order to disclose other information cited within theother publications referred to within WO90/12814. To carry out theinvention these insulins must be in a monomeric form or take a monomericform quickly in a human.

[0108] U.S. patent application Ser. No. 074,558 discloses a superactivehuman insulin analog, [10-Aspartic Acid-B] human insulin, which hasincreased activity over natural human insulin. Specifically,[10-Aspartic Acid-B] human insulin was determined to be 4 to 5 timesmore potent than natural insulins. U.S. patent application Serial No.273,957 and International Application Serial No. PCT/US88/02289 discloseother superactive insulin analogs, des-pentapeptide(B26-B30)-[Asp^(B10), Tyr^(B25)-α-carboxamide] human insulin,(B26-B30)-[Glu^(B10), Tyr^(B25)-α-carboxamidel] human insulin, andfurther insulin analogs of the formula des(B26-B30)-[X^(B10),Tyr^(B25)-α-carboxamide] human insulin, in which X is a residuesubstituted at position 10 of the B chain. These insulin analogs havepotencies anywhere from 11 to 20 times that of natural human insulin.All of the above-described insulin analogs involve amino acidsubstitutions along the A or B chains of natural human insulin, whichincrease the potency of the compound or change other properties of thecompound.

[0109] Other than insulin lispro the insulin analogs are not presentlyused for the treatment of patients on a commercial scale. However,insulin lispro and other insulin analogs being developed could be usedwith the present invention in that the present invention can be used toprovide variable dosing in response to currently measured serum glucoselevels. Further, since many insulin analogs are more potent thanconventional insulin, their delivery via the intrapulmonary route isparticularly convenient.

[0110] Information regarding dosing insulin can be found withinHarrison's—Principles of Internal Medicine (most recent edition) and theDrug Evaluation Manual, 1993 (AMA-Division of Drugs and Toxicology),both of which are published by McGraw Hill Book Company, New York,incorporated herein by reference to disclose conventional informationregarding dosing of insulin.

Monitoring Diabetic Control

[0111] All methods of treating diabetes involve measuring glucose levelsin some manner. Such measurements are necessary in order to titrateproper dosing and avoid the over-administration of insulin which canresult in fatal hypoglycemia. Measurements of urine glucose alone areinsufficient to assess diabetic control and bring mean plasma glucosevalues into a near normal range since the urine will be free of glucosewhen the plasma concentration is relatively normal. For this reason,“home glucose monitoring” is used in those patients treated bycontinuous subcutaneous insulin infusion (CSII) or multiple subcutaneousinjection (MSI) techniques. Such monitoring requires capillary bloodwhich can be obtained in a substantially painless manner using a smallspring-triggered device referred to as Autolet™ produced by UlstrScientific Incorporated which device is equipped with small disposablelancelets. The amount of glucose is analyzed using chemicallyimpregnated strips which are read in a commercially availablereflectance meter. One commercially available strip is referred to asChemstrip bG (produced by Bio-Dynamics). The Chemstrip Bg can providesatisfactory values by visual inspection utilizing a dual-color scale,thus eliminating the need for a reflectance meter. Frequent measurementof the plasma glucose (a fairly standard program utilizes seven or eightassays over a 24-hour period) allows a reasonable assessment of meanplasma glucose levels during the day and guides adjustment of insulindosage.

[0112] The methodology of the present invention is preferably utilizedin combination with a closely controlled means of monitoring serumglucose levels. More specifically, the invention is used to administerdoses of monomeric insulin via the intrapulmonary route. The doses maybe administered more frequently but in somewhat smaller amounts than aregenerally administered by injection. The amount of insulin and monomericinsulin administered can be readily adjusted in that smaller amounts aregenerally administered using the intrapulmonary delivery methodology ofthe present invention.

[0113] During the day, as insulin is administered, serum glucose levelsare frequently monitored. The amount of insulin administered can bedosed based on the monitored serum glucose levels, i.e., as glucoselevels increase, the amount of insulin can be increased, and as glucoselevels are seen to decrease, the dosing of insulin can be decreased.

[0114] Based on the information disclosed herein in combination withwhat is known about insulin dosing and serum glucose levels, computerreadable programs can be readily developed which can be used inconnection with the insulin delivery device of the present invention.More specifically, a microprocessor of the type disclosed in U.S. Pat.No. 5,542,410 can be programmed so as to deliver precise doses ofinsulin which correspond to the particular needs of the patient based onserum glucose monitoring information which is supplied to themicroprocessor. Further, the dosing information contained within themicroprocessor can be fed to a separate computer and/or serum glucosemonitoring device (preferably portable) in order to calculate the besttreatment and dosing schedule for the particular patient.

Insulin Containing Formulations

[0115] A variety of different monomeric insulin containing formulationscan be used in connection with the present invention. The activeingredient within such formulations is monomeric insulin which can becombined with regular insulin. Further, the monomeric insulin may becombined with an insulin analog which is an analog of human insulinwhich has been recombinantly produced. Although the monomeric insulin isgenerally present by itself as the sole active ingredient, it may bepresent with an additional active ingredient such as a sulfonylurea.However, such sulfonylureas are generally administered separately inorder to more closely control dosing and serum glucose levels.

[0116] The present invention provides a great deal of flexibility withrespect to the types of monomeric insulin formulations to beadministered. For example, a container can include monomeric insulin byitself or in combination with an analog of any type or combinations ofdifferent insulin analogs. Further, a package can be created whereinindividual containers include different formulations wherein theformulations are designed to achieve a particular effect e.g., fastacting insulin or quick absorbing insulin. The patient along with thecare giver and careful monitoring can determine the preferred insulindosing protocol to be followed for the particular patient.

[0117] The monomeric insulin may be provided as a dry powder by itself,and in accordance with another formulation, the insulin or activeingredient is provided in a solution formulation. The dry powder couldbe directly inhaled by allowing inhalation only at the same measuredinspiratory flow rate and inspiratory volume for each delivery. However,the powder is preferably dissolved in an aqueous solvent to create asolution which is moved through a porous membrane to create an aerosolfor inhalation.

[0118] Any formulation which makes it possible to produce aerosolizedforms of monomeric insulin which can be inhaled and delivered to apatient via the intrapulmonary route can be used in connection with thepresent invention. Specific information regarding formulations (whichcan be used in connection with aerosolized delivery devices) isdescribed within Remington's Pharmaceutical Sciences, A. R. Gennaroeditor (latest edition) Mack Publishing Company. Regarding insulinformulations, it is also useful to note Sciarra et al. [Journal ofPharmaceutical Sciences, Vol. 65, No. 4, 1976].

[0119] The monomeric insulin is preferably included in a solution suchas the type of solution which is made commercially available forinjection and/or other solutions which are more acceptable forintrapulmonary delivery. When preparing preferred formulations of theinvention which provide for the monomeric insulin, excipient andsolvent, any pharmaceutically acceptable excipient may be used providedit is not toxic in the respiratory tract. The monomeric insulinformulation preferably has a pH of about 7.4±1.0.

[0120] Formulations include monomeric insulin dry powder by itselfand/or with an excipient. When such a formulation is used, it may beused in combination with a gas propellant which gas propellant isreleased over a predetermined amount of dried powder which is forcedinto the air and inhaled by the patient. It is also possible to designthe device so that a predetermined amount of dry powder is placed behinda gate. The gate is opened in the same manner as the valve is releasedso that the same inspiratory flow rate and inspiratory volume isrepeatedly obtained. Thereafter, the dry powder is inhaled by thepatient and the insulin is delivered.

[0121] Rapidly acting preparations are always indicated in diabeticemergencies and in CSII and MSI programs. Intermediate preparations areused in conventional and MSI regimens. It is not possible to delineateprecisely the biologic responses to the various preparations becausepeak effects and duration vary from patient to patient and depend notonly on route of administration but on dose. The various insulins areavailable as rapid (regular, semilente), intermediate (NPH, lente,globin), and long-acing (PZI, ultralente) preparations, although not allmanufacturers offer all varieties. Lente and NPH insulin are used inmost conventional therapy and are roughly equivalent in biologiceffects. These can be used with monomeric insulin.

[0122] The methodology of the invention may be carried out using aportable, hand-held, battery-powered device which uses a microprocessorcomponent as disclosed in U.S. Pat. No. 5,404,871, issued Apr. 11, 1995and U.S. Pat. No. 5,450,336, issued Sep. 12, 1995 both of which areincorporated herein by reference. In accordance with another system themethodology of the invention could be carried out using the device,dosage units and system disclosed in U.S. Ser. No. 94/05825 withmodifications as described herein. Monomeric insulin is included in anaqueous formulation which is aerosolized by moving the formulationthrough a flexible porous membrane. Alternatively, the methodology ofthe invention could be carried out using a mechanical (non-electronic)device. Those skilled in the art recognized that various components canbe mechanical set to actuate at a given inspiratory flow rate (e.g. aspring biased valve) and at a given volume (e.g. a spinable flywheelwhich rotates a given amount per a given volume). The components of suchdevices could be set to allow drug release inside defined parameters.

[0123] The monomeric insulin which is released to the patient may be ina variety of different forms. For example, the insulin may be an aqueoussolution of drug, i.e., drug dissolved in water and formed into smallparticles to create an aerosol which is delivered to the patient.Alternatively, the drug may be in a solution or a suspension wherein alow-boiling point propellant is used as a carrier fluid. In yet, anotherembodiment the insulin may be in the form of a dry powder which isintermixed with an airflow in order to provide for delivery of drug tothe patient. Regardless of the type of drug or the form of the drugformulation, it is preferable to create drug particles having a size inthe range of about 0.5 to 12 microns, more preferably 1-4 microns. Bycreating drug particles which have a relatively narrow range of size, itis possible to further increase the efficiency of the drug deliverysystem and improve the repeatability of the dosing. Thus, it ispreferable that the particles not only have a size in the range of 0.5to 12 microns but that the mean particle size be within a narrow rangeso that 80% or more of the particles being delivered to a patient have aparticle diameter which is within ±20% of the average particle size,preferably ±10% and more preferably ±5% of the average particle size.

[0124] An aerosol may be created by forcing drug through pores of amembrane which pores have a size in the range of about 0.25 to 6 micronspreferably 0.5 to 3.0 microns. When the pores have this size theparticles in the aerosol will have a diameter about twice the diameterof the pore opening from which the formulation exits. However, theparticle size can be substantially reduced by adding heat to the airaround the particles and cause evaporation of carrier. Drug particlesmay be released with an air flow intended to keep the particles withinthis size range. The creation of small particles may be facilitated bythe use of the vibration device which provides a vibration frequency inthe range of about 800 to about 4000 kilohertz. Those skilled in the artwill recognize that some adjustments can be made in the parameters suchas the size of the pores from which drug is released, vibrationfrequency and amplitude, pressure, and other parameters based on theconcentration, density, viscosity and surface tension of the formulationkeeping in mind that the object is to provide aerosolized particleshaving a diameter in the range of about 0.25 to 12 microns, preferably1.0-3.0 microns.

[0125] The drug formulation may be a low viscosity liquid formulation.The viscosity of the drug by itself or in combination with a carrier isnot of particular importance except to note that the formulationpreferably has characteristics such that it can be forced out ofopenings of the flexible or convex membrane to form an aerosol, e.g.,using 20 to 400 psi to form an aerosol preferably having a particle sizein the range of about 0.5 to 6.0 microns.

[0126] Drug may be stored in and/or released from a container of anydesired size. In most cases the size of the container is not directlyrelated to the amount of drug being delivered in that most formulationsinclude relatively large amounts of excipient material e.g. water or asaline solution. Accordingly, a given size container could include awide range of different doses by varying drug concentration.

[0127] Drug containers may include indices which may be electronic andmay be connected to a power source such as a battery. When the indicesare in the form of visually perceivable numbers, letters or any type ofsymbol capable of conveying information to the patient. Alternatively,the indices may be connected to a power source such as a battery whenthe indices are in the form of magnetically, optically or electronicallyrecorded information which can be read by a drug dispensing device whichin turn provides visual or audio information to the user. The indicescan be designed for any desired purpose but in general provide specificinformation relating to the day and/or time when the drug within acontainer should be administered to the patient. Such indices mayrecord, store and transfer information to a drug dispensing deviceregarding the number of doses remaining in the container. The containersmay include labeling which can be in any format and could include daysof the month or other symbols or numbers in any variation or language.

[0128] In addition to disclosing specific information regarding the dayand time for drug delivery the indices could provide more detailedinformation such as the amount of insulin dispensed from each containerwhich might be particularly useful if the containers included differentamounts of insulin. The device may dispense all or any desiredpercentage amount (1-100%) of the insulin in the container. The devicekeeps a record of the amount dispensed and the container can be reusedwithin a given period of time (e.g., 2 hours or less) to dispense theremainder of the insulin in a given container. However, it is preferableto discard a container after use even if all the formulation is notexpelled. This ensures freshness and reduces contamination. Further,magnetic, optical and/or electronic indices could have new informationrecorded onto them which information could be placed there by the drugdispensing device. For example, a magnetic recording means could receiveinformation from the drug dispensing device indicating the precise time(and amount) which the insulin was actually administered to the patient.In addition to recording the time of delivery the device could monitorthe expected efficacy of the delivery based on factors such as theinspiratory flow rate which occurred following the initial release ofinsulin. The information recorded could then be read by a separatedevice, interpreted by the care-giver and used to determine theusefulness of the present treatment methodology. For example, if theglucose levels of the patient did not appear to be responding well butthe recorded information indicating that the patient had taken the drugat the wrong time or that the patient had misdelivered drug by changinginspiratory flow rate after initial release it might be determined thatfurther education in patient use of the device was needed but that thepresent dosing methodology might well be useful. However, if therecordings indicated that the patient had delivered the aerosolizedinsulin using the proper techniques and still not obtained the correctresults (e.g. acceptable glucose levels) another dosing methodologymight be recommended. The method of treating diabetes mellitus may becarried out using a hand-held, portable device comprised of (a) a devicefor holding a disposable package comprised of at least one butpreferably a number of drug containers, (b) a propellant or a mechanicalmechanism for moving the contents of a container through a porousmembrane (c) a monitor for analyzing the inspiratory flow rate andvolume of a patient, and (d) a switch for automatically releasing orfiring the mechanical means after the inspiratory flow and/or volumereaches a threshold level. The device may also include a transportmechanism to move the package from one container to the next with eachcontainer and its porous membrane being disposed of after use.Containers are preferably used only 1,2,3 or 4 times, at most. If usedmore than once, the remainder in the container is used in 2 hours orless and/or disposed of. The entire device is self-contained,light-weight (less than 1 kg preferably less than 0.5 kg loaded) andportable.

[0129] The device may include a mouth piece at the end of the flow path,and the patient inhales from the mouth piece which causes an inspiratoryflow to be measured within the flow path which path may be in anon-linear flow-pressure relationship. This inspiratory flow causes anairflow air flow transducer to generate a signal. This signal isconveyed to a microprocessor which is able to convert, continuously, thesignal from the transducer in the inspiratory flow path to a flow ratein liters per minute. The microprocessor can further integrate thiscontinuous air flow rate signal into a representation of cumulativeinspiratory volume. At an appropriate point in the inspiratory cycle,the microprocessor can send a signal to an actuation means (and/or avibration device below the resonance cavity). When the actuation meansis signaled, it causes the mechanical means (by pressure and/orvibration) to move drug from a container on the package into theinspiratory flow path of the device and ultimately into the patient'slungs. After being released, the drug and carrier will pass through aporous membrane, which can be vibrated to aerosolize the formulation andthereafter enter the lungs of the patient.

[0130] It is important to note that the firing threshold of the deviceis not based on a single criterion such as the rate of air flow throughthe device or a specific time after the patient begins inhalation. Thefiring threshold is preferably based on repeating the firing at the sameflow rate and volume. This means that the microprocessor controlling thedevice takes into consideration the instantaneous air flow rate as wellas the cumulative inspiratory flow volume. Both are simultaneouslyconsidered together in order to determine the optimal point in thepatient's inspiratory cycle most preferable in terms of (1) reproduciblydelivering the same amount of drug to the patient with each release ofdrug by releasing drug at the same point each time and (2) maximizingthe amount of drug delivered as a percentage of the total amount of drugreleased by releasing with the parameters described herein.

[0131] The device preferably includes a means for recording acharacterization of the inspiratory flow profile for the patient whichis possible by including a microprocessor in combination with aread/write memory means and a flow measurement transducer. By using suchdevices, it is possible to change the firing threshold at any time inresponse to an analysis of the patient's inspiratory flow profile, andit is also possible to record drug dosing events over time. In aparticularly preferred embodiment the characterization of theinspiratory flow can be recorded onto a recording means associated withdisposable package.

[0132] The details of a drug delivery device which includes amicroprocessor and pressure transducer of the type which may be used inconnection with the present invention are described and disclosed withinU.S. Pat. No. 5,404,871, issued Apr. 11, 1995 and U.S. Pat. No.5,450,336, issued Sep. 12, 1995 incorporated in their entirety herein byreference, and specifically incorporated in order to describe anddisclose the microprocessor and program technology used therewith. Thepre-programmed information is contained within a nonvolatile memorywhich can be modified via an external device. In another embodiment,this pre-programmed information is contained within a “read only” memorywhich can be unplugged from the device and replaced with another memoryunit containing different programming information. In yet anotherembodiment, a microprocessor, containing read only memory which in turncontains the pre-programmed information, is plugged into the device. Foreach of these embodiments, changing the programming of the memory devicereadable by a microprocessor will radically change the behavior of thedevice by causing the microprocessor to be programmed in a differentmanner. This is done to accommodate different insulin formulation andfor different types of treatment, e.g., patients with different types ofdiabetes.

[0133] After dosing a patient with insulin it is desirable to measureglucose (invasively or non-invasively) and make adjustments as needed toobtain the desired glucose level.

[0134] In accordance with all methods the patient does not push a buttonto release drug. The drug is released automatically by signals from themicroprocessor using measurements obtained.

[0135] The doses administered are based on an assumption that whenintrapulmonary delivery methodology is used the efficiency of thedelivery is at a known percent amount, e.g., approximately 20% to 50% ormore and adjustments in the amount released in order to take intoaccount the efficiency of the device. The differential between theamount of insulin actually released from any device and the amountactually delivered to the patient varies due to a number of factors. Ingeneral, devices used with the present invention can have an efficiencyas low as 10% and as high as 50% or more meaning that as little as 10%of the released insulin may actually reach the circulatory system of thepatient and as much as 50% or more might be delivered. The efficiency ofthe delivery will vary somewhat from patient to patient and must betaken into account when programming the device for the release ofinsulin. In general, a conventional metered (propellant-driven) doseinhaling device is about 10% efficient.

[0136] One of the features and advantages of the present invention isthat the microprocessor can be programmed to take a variety of differentcriteria into consideration with respect to dosing times. Specifically,the microprocessor can be programmed so as to include a minimum timeinterval between doses i.e. after a given delivery another dose cannotbe delivered until a given period of time has passed. Secondly, thetiming of the device can be programmed so that it is not possible toexceed the administration of a set maximum amount of insulin within agiven time. For example, the device could be programmed to preventdispersing more than 5 units of insulin within one hour. Moreimportantly, the device can be programmed to take both criteria intoconsideration. Thus, the device can be programmed to include a minimumtime interval between doses and a maximum amount of insulin to bereleased within a given time period. For example, the microprocessorcould be programmed to allow the release of a maximum of 5 units ofinsulin during an hour which could only be released in amounts of 1 unitwith each release being separated by a minimum of five minutes.

[0137] Additional information regarding dosing with insulin viainjection can be found within Harrison's—Principles of Internal Medicine(most recent edition) published by McGraw Hill Book Company, New York,incorporated herein by reference to disclose conventional informationregarding dosing insulin via injection.

[0138] Another feature of the device is that it may be programmed not torelease drug if it does not receive a signal transmitted to it by atransmitter worn by the intended user. Such a system improves thesecurity of the device and prevents misuse by unauthorized users such aschildren.

[0139] The microprocessor of the invention can be connected to externaldevices permitting external information to be transferred into themicroprocessor of the invention and stored within the non-volatileread/write memory available to the microprocessor. The microprocessor ofthe invention can then change its drug delivery behavior based on thisinformation transferred from external devices such as a glucosemonitoring device. All of the features of the invention are provided ina portable, programmable, battery-powered, hand-held device for patientuse which has a size which compares favorably with existing metered doseinhaler devices.

[0140] Different mechanisms will be necessary in order to deliverdifferent formulations, such as a dry powder without any propellant. Adevice could be readily designed so as to provide for the mechanicalmovement of a predetermined amount of dry powder to a given area. Thedry powder would be concealed by a gate, which gate would be opened inthe same manner described above, i.e., it would be opened when apredetermined flow rate level and cumulative volume have been achievedbased on an earlier monitoring event. Patient inhalation or other sourceof energy such as from compressed gas or a mechanical device would thencause the dry powder to form a dry dust cloud and be inhaled.

[0141] In addition to monitoring glucose levels in order to determineproper insulin dosing, the microprocessor of the present invention isprogrammed so as to allow for monitoring and recording data from theinspiratory flow monitor without delivering drug. This is done in orderto characterize the patient's inspiratory flow profile in a given numberof monitoring events, which monitoring events preferably occur prior todosing events. After carrying out a monitoring event, the preferredpoint within the inspiratory cycle for drug delivery can be calculated.This calculated point is a function of measured inspiratory flow rate aswell as calculated cumulative inspiratory flow volume. This informationis stored and used to allow activation of the valve when the inhalationcycle is repeated during the dosing event. Those skilled in the art willalso readily recognize that different mechanisms will be necessary inorder to deliver different formulations, such as a dry powder withoutany propellant. A device could be readily designed so as to provide forthe mechanical movement of a predetermined amount of dry powder to agiven area. The dry powder would be concealed by a gate, which gatewould be opened in the same manner described above, i.e., it would beopened when a predetermined flow rate level and cumulative volume havebeen achieved based on an earlier monitoring event. Patient inhalationwould then cause the dry powder to form a dry dust cloud and be inhaled.Dry powder can also be aerosolized by compressed gas, and a solution canbe aerosolized by a compressed gas released in a similar manner and theninhaled.

EXAMPLES

[0142] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow to make and use various constructs and perform the various methodsof the present invention and are not intended to limit the scope of whatthe inventors regard as their invention. Efforts have been made toensure accuracy with respect to numbers used (e.g. amounts,concentrations, particular components, etc.) but some deviations shouldbe accounted for.

EXAMPLE 1 Administration of Regular Recombinant Human Insulin

[0143] A study was performed to determine the influence of differentinhalation maneuvers: deep (V_(H)) and shallower (V_(L)) inhalation.Deep inhalations required the patients to inhale as much as possible(e.g., 4-5 liters) and shallow inhalation were about half that (e.g.2-2.5 liters) following the administration of aerosolized drug). Thestudy was performed using five healthy, fasting male subjects. To eachof the subjects, 250 U/ml of a 7.4 pH human zinc insulin formulation wasadministered using three methods: subcutaneous administration, deepinhalation administration, or shallow inhalation administration.

[0144] The study was performed using five healthy, fasting malesubjects. 250 U/ml of a 3.5 pH human insulin formulation wasadministered to each of the subjects using three methods: subcutaneousadministration, V_(H) inhalation administration and V_(L)administration. Subcutaneous administration of the insulin consisted ofan injection of a predetermined dosage into the subcutaneous region ofthe abdominal area. Aerosol administration to each subject was performedusing a unit-dosed, breath-actuated microprocessor controlled device(AERx™), such as the device disclosed in the present application (seeU.S. Pat. No. 5,660,166 issued Aug. 26. 1997).

[0145] Serial serum blood samples were taken from each subject for theanalysis of plasma glucose. The inhalation method resulted in a morerapid initial change, and experienced a plateau at approximately a −20%change in plasma glucose. The subcutaneous administration resulted in aslower response initially, achieving a later plateau at approximately a−25% change in glucose response.

[0146] The pharmacokinetic parameters—C_(max), the maximum serum insulinconcentration achieved in each subject, and T_(max), the amount of timeneeded for subjects to reach C_(max) after administration weredetermined for each subject, and (summarized in Table 1). The deepinhalation method showed a 10-fold decrease in T_(max). TABLE 1 Inhaledhuman insulin: effect of mode of administration Parameter (mean ± SD)AERx-V_(H) AERx-V_(L) T_(max) (min) 5 ± 6 51 ± 18 C_(max) (μU/ml) 26.7 ±9.1  20.9 ± 8.1 

[0147] Serum insulin profiles of each of the three modes ofadministration show similar peaks before tapering off over a three hourperiod (FIG. 1). The AERx device V_(H) administration peaks much soonerand at a higher concentration than the other methods, peaking atapproximately 26 μU/ml at about 20 minutes. The AERx device V_(L)administration results in a slightly later and lower peak at one hour.Subcutaneous injection also results in a later peak.

[0148] The study conducted with the regular zinc insulin pH 7.4 showedthe importance of the breathing technique in the administration of thisparticular insulin formulation, as controlled, deep breathing promotedrapid insulin absorption.

[0149] The results of experiment 1 demonstrate one aspect of the presentinvention. Specifically, the results show that it is important tocontrol the inhaled volume when inhaling an aerosolized dose of regularinsulin. Thus, one aspect of the invention involves measuring apatient's inhaled volume at delivery in order (1) repeatedly deliverwith the same inhaled volume each time to ensure repeatability ofdosing; and (2) prompt the patient to inhale a high volume, e.g. 80%plus or minus 15% of lung capacity with each inhalation. The promptingto inhale a high volume can be carried out by sending a signal to thepatient from a device which measures the inspiratory volume during drugdelivery.

EXAMPLE 2 Determination of Efficacy of Administration of AerosolizedHuman Insulin Lispro Modes of Administration

[0150] Pharmacokinetic parameters associated with the two modes ofinsulin administration, inhalation of aerosolized insulin lispro andsubcutaneous injection of insulin lispro, were determined to compare theefficacy (bioeffectiveness in reducing glucose levels) and speed ofeach. The study was performed using nine healthy, fasted male subjects.

[0151] Aerosol administration to each subject was performed using theAERx™ device. Administration was done using both deep (V_(H)) andshallower (V_(L)) inhaled administration—in 5 out of 9 subjects.Subcutaneous administration of the insulin lispro consisted of aninjection of a predetermined dosage into the subcutaneous region of theabdominal area. Serial serum blood samples were taken from each subjectfor the analysis of plasma glucose and serum insulin.

[0152] The pharmacokinetic parameters C_(max) and T_(max) weredetermined for each subject. (Table 2). T_(max) was earlier followinginhalation administration of insulin lispro, indicating a more rapidabsorption from the lung as compared to SC administration. Thus, themode of inhalation (V_(H) or V_(L)) did not appear to significantlyeffect pharmacokinetics of the delivery of inhaled insulin lispro ascompared to the affect of V_(L) and V_(H) on the delivering of regularinsulin. TABLE 2 Pharmacokinetic parameters after insulin lisproadministration (systematic study, n = 5) Parameter AERx-V_(H) AERx-V_(L)(mean ± SD) (0.3 U/kg) (0.3 U/kg) T_(max) (min) 9 ± 2 18 ± 15 C_(max)(μU/ml) 46 ± 12 49 ± 12

[0153] In contrast to data obtained for aerosolized delivery of regularhuman insulin, the mode of inhalation did not lead to changes in theserum insulin levels following administration of insulin lispro—compareFIGS. 1 and 2.

[0154] The results in Tables 1 and 2 can be compared to show that thetotal inhaled volume at delivery greatly effects results whenadministering regular human recombinant insulin (Table 1) but has muchless of an effect when administering insulin lispro. As shown in FIG. 2,the blood concentration versus time insulin lispro is virtually the samefor both the V_(H) and V_(L) maneuvers. This surprising result indicatesthat repeatability of dosing can be more readily obtained with theadministration of insulin lispro by inhalation as compared withconventional insulin by inhalation. The results shown here indicate thatwhen delivering insulin (not monomeric insulin) by inhalation the totalinhaled volume should be about the same at each delivery to obtainrepeatable delivery. Thus, referring to FIG. 3, insulin is released atthe same point 1 for each release and then the patient continues toinhale to the same point 3 or 4. Preferably, the patient continues toinhale to point 4 or higher each time to obtain repeatable delivery.

[0155] The foregoing invention has been described in some detail by wayof illustration and example for purposes of clarity of understanding.The instant invention is shown herein in what is considered to be themost practical and preferred embodiments. It is recognized, however,that departures may be made therefrom which are within the scope of theinvention and that obvious modifications will occur to one skilled inthe art upon reading this disclosure. Accordingly, the invention islimited only by the following claims.

What is claimed:
 24. A method of treating diabetes mellitus in a patientin need thereof, said method comprising: (a) supplying a predeterminedamount of insulin to a hand held device, said predetermined amount beingin excess of that amount required, in the bloodstream of said patient,to produce or maintain an acceptable serum glucose level in saidpatient; (b) contacting said insulin with a compressed gas to form acloud in said hand held device, said cloud comprising a repeatableamount of insulin, said repeatable amount being in excess of that amountrequired, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level in said patient; and (c) inhaling saidcloud at an inspiratory flow rate and volume adapted to deliver aportion of said cloud to the lungs of said patient, wherein an amount ofsaid insulin in said cloud effective, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level insaid patient is absorbed into the bloodstream of said patient.
 25. Amethod of treating diabetes mellitus in a patient in need thereof, saidmethod comprising: (a) supplying a predetermined amount of insulin to ahand held device, said predetermined amount being in excess of thatamount required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level in said patient; (b)contacting said insulin with a compressed gas to form a cloud in saidhand held device, said cloud comprising a repeatable and controlledamount of insulin, said repeatable and controlled amount being in excessof that amount required, in the bloodstream of said patient, to produceor maintain an acceptable serum glucose level in said patient; and (c)inhaling said cloud at an inspiratory flow rate and volume adapted todeliver a portion of said cloud to the lungs of said patient, wherein anamount of insulin in said cloud effective, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level insaid patient is absorbed into the bloodstream of said patient.
 26. Amethod of treating diabetes mellitus in a patient in need thereof, saidmethod comprising: (a) mechanically supplying a predetermined amount ofinsulin to a given area of a hand held device, said predetermined amountbeing in excess of that amount required, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level insaid patient; (b) aerosolizing said insulin with a compressed gas toform a cloud in said hand held device, said cloud comprising arepeatable and controlled amount of insulin, said repeatable andcontrolled amount being in excess of that amount required, in thebloodstream of said patient, to produce or maintain an acceptable serumglucose level in said patient; and (c) inhaling said cloud at aninspiratory flow rate and volume adapted to deliver a portion of saidcloud to the lungs of said patient, wherein an amount of insulin in saidcloud effective, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level in said patient is absorbedinto the bloodstream of said patient.
 27. A method of treating diabetesmellitus in a patient in need thereof, said method comprising: (a)supplying a predetermined amount of insulin in the form of a dry powderto a hand held device, said predetermined amount being in excess of thatamount required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level in said patient; (b)contacting said insulin with a compressed gas to form a cloud in saidhand held device, said cloud comprising a repeatable and controlledamount of insulin, said repeatable and controlled amount being in excessof that amount required, in the bloodstream of said patient, to produceor maintain an acceptable serum glucose level in said patient; and (c)inhaling said cloud at an inspiratory flow rate and volume adapted todeliver a portion of said cloud to the lungs of said patient, wherein anamount of insulin in said cloud effective, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level insaid patient is absorbed into the bloodstream of said patient.
 28. Amethod of treating diabetes mellitus in a patient in need thereof, saidmethod comprising: (a) mechanically supplying a predetermined amount ofinsulin in the form of a dry powder to a given area of a hand helddevice, said predetermined amount being in excess of that amountrequired, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level in said patient; (b) aerosolizing saidinsulin with a compressed gas to form a cloud in said hand held device,said cloud comprising a repeatable and controlled amount of insulin,said repeatable and controlled amount being in excess of that amountrequired, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level in said patient; and (c) inhaling saidcloud at an inspiratory flow rate and volume adapted to deliver aportion of said cloud to the lungs of said patient, wherein an amount ofinsulin in said cloud effective, in the bloodstream of said patient, toproduce or maintain an acceptable serum glucose level in said patient isabsorbed into the bloodstream of said patient.
 29. A method of treatingdiabetes mellitus in a patient in need thereof, said method comprising:(a) supplying a predetermined amount of insulin in the form of a drypowder to a hand held device, said predetermined amount being 2 to 10times that amount required, in the bloodstream of said patient, toproduce or maintain an acceptable serum glucose level in the blood ofsaid patient; (b) contacting said insulin with a compressed gas to forma dry cloud in said hand held device, said cloud comprising a repeatableand controlled amount of insulin, said repeatable and controlled amountbeing 2 to 10 times that amount required, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level in theblood of said patient; and (c) inhaling said cloud at an inspiratoryflow rate and volume adapted to deliver a portion of said cloud to thelungs of said patient, wherein an amount of insulin in said cloudeffective, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level in said patient is absorbed into thebloodstream of said patient.
 30. A method of treating diabetes mellitusin a patient in need thereof, said method comprising: (a) mechanicallysupplying a predetermined amount of insulin in the form of a dry powderto a given area of a hand held device, said predetermined amount being 2to 10 times that amount required, in the bloodstream of said patient, toproduce or maintain an acceptable serum glucose level in said patient;(b) aerosolizing said insulin with a compressed gas to form a dry cloudin said hand held device, said cloud comprising a repeatable andcontrolled amount of insulin, said repeatable and controlled amountbeing 2 to 10 times that amount required, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level in theblood of said patient; and (c) inhaling said cloud at an inspiratoryflow rate and volume adapted to deliver a portion of said cloud to thelungs of said patient, wherein an amount of insulin in said cloudeffective, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level in said patient is absorbed into thebloodstream of said patient.
 31. A method of treating diabetes mellitusin a patient in need thereof, said method comprising: (a) supplying apredetermined amount of insulin in the form of a dry powder to a handheld device, said predetermined amount being 2 to 10 times that amountrequired, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level in said patient; (b) contacting saidinsulin with a compressed gas to form a dry cloud in said hand helddevice, said cloud comprising a repeatable and controlled amount ofinsulin, said repeatable and controlled amount being 2 to 10 times thatamount required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level in the blood of said patient;and (c) inhaling said cloud at an inspiratory flow rate and volumeadapted to deliver a portion of said cloud to the lungs of said patient,wherein 1 to 30 units of insulin are absorbed into the bloodstream ofsaid patient.
 32. A method of treating diabetes mellitus in a patient inneed thereof, said method comprising: (a) mechanically supplying apredetermined amount of insulin in the form of a dry powder to a givenarea of a hand held device, said predetermined amount being 2 to 10times that amount required, in the bloodstream of said patient, toproduce or maintain an acceptable serum glucose level in said patient;(b) aerosolizing said insulin with a compressed gas to form a dry cloudin said hand held device, said cloud comprising a repeatable andcontrolled amount of insulin, said repeatable and controlled amountbeing 2 to 10 times that amount required, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level in theblood of said patient; and (c) inhaling said cloud at an inspiratoryflow rate and volume adapted to deliver a portion of said insulin cloudto the lungs of said patient, wherein 1 to 30 units of insulin areabsorbed into the bloodstream of said patient.
 33. A method of treatingdiabetes mellitus in a patient in need thereof, said method comprising:(a) supplying a predetermined amount of insulin in the form of a drypowder to a hand held device, said predetermined amount being 2 to 300units of insulin; (b) contacting said insulin with a compressed gas toform a dry cloud in said hand held device, said cloud comprising arepeatable and controlled amount of insulin, said repeatable andcontrolled amount being 2 to 300 units of insulin; and (c) inhaling saidcloud at an inspiratory flow rate and volume adapted to deliver aportion of said cloud to the lungs of said patient; wherein 1 to 30units of insulin are repeatably absorbed into the bloodstream of saidpatient.
 34. A method of treating diabetes mellitus in a patient in needthereof, said method comprising: (a) mechanically supplying apredetermined amount of insulin in the form of a dry powder to a givenarea of a hand held device, said predetermined amount being 2 to 300units of insulin; (b) aerosolizing said insulin with a compressed gas toform a dry cloud in said hand held device, said cloud comprising arepeatable and controlled amount of insulin, said repeatable andcontrolled amount being 2 to 300 units of insulin; and (c) inhaling saidcloud at an inspiratory flow rate and volume adapted to deliver aportion of said cloud to the lungs of said patient; wherein 1 to 30units of insulin are repeatably absorbed into the bloodstream of saidpatient.
 35. A method of treating diabetes mellitus in a patient in needthereof, said method comprising: (a) determining the amount of insulinrequired, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level; (b) aerosolizing, in a hand held device,a predetermined amount of insulin in excess of said required amount ofinsulin with a compressed gas to form a cloud in said hand held device,said cloud comprising a repeatable amount of insulin in excess of saidrequired amount of insulin; and (c) inhaling said cloud at aninspiratory flow rate and volume adapted to deliver a portion of saidinsulin cloud to the lungs of said patient, wherein said required amountof insulin is absorbed into the bloodstream of said patient.
 36. Amethod of treating diabetes mellitus in a patient in need thereof, saidmethod comprising: (a) determining the amount of insulin required, inthe bloodstream of said patient, to produce or maintain an acceptableblood glucose level; (b) aerosolizing, in a hand held device, apredetermined amount of insulin in excess of said required amount ofinsulin with a compressed gas to form a cloud in said hand held device,said cloud comprising a repeatable and controlled amount of insulin inexcess of said required amount of insulin; and (c) inhaling said cloudat an inspiratory flow rate and volume adapted to deliver a portion ofsaid cloud to the lungs of said patient, wherein said required amount ofinsulin is absorbed into the bloodstream of said patient.
 37. A methodof treating diabetes mellitus in a patient in need thereof, said methodcomprising: (a) determining the amount of insulin required, in thebloodstream of said patient, to produce or maintain an acceptable serumglucose level; (b) aerosolizing, in a hand held device, a predeterminedamount of insulin 2 to 10 times said required amount of insulin with acompressed gas to form a dry cloud in said hand held device, said cloudcomprising a repeatable and controlled amount of insulin, saidrepeatable and controlled amount being 2 to 10 times said requiredamount of insulin; and (c) inhaling said cloud at an inspiratory flowrate and volume adapted to deliver a portion of said cloud to the lungsof said patient, wherein said required amount of insulin is absorbedinto the bloodstream of said patient.
 38. A method of treating diabetesmellitus in a patient in need thereof, said method comprising: (a)determining the amount of insulin required, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level, saidrequired amount being 1-30 units; (b) aerosolizing, in a hand helddevice, a predetermined amount of a dry powder comprising insulin, saidpredetermined amount being 2 to 10 times said required amount ofinsulin, with a compressed gas to form a dry cloud in said hand helddevice, said cloud comprising a repeatable and controlled amount ofinsulin, said repeatable and controlled amount being 2 to 10 times saidrequired amount of insulin; and (c) inhaling said cloud at aninspiratory flow rate and volume adapted to deliver a portion of saidcloud to the lungs of said patient, wherein from 1 to 30 units ofinsulin are absorbed into the bloodstream of said patient.
 39. A methodof treating diabetes mellitus in a patient in need thereof, said methodcomprising: (a) determining the amount of insulin required, in thebloodstream of said patient, to produce or maintain an acceptable serumglucose level, said required amount being from 1-30 units; (b)aerosolizing, in said hand held device, a predetermined amount ofinsulin in the form of a dry powder, said predetermined amount beingfrom 2 to 300 units of insulin, with a compressed gas to form a drycloud in said hand held device, said cloud comprising a repeatable andcontrolled amount of insulin, said repeatable and controlled amountbeing from 2 to 300 units of insulin; and (c) inhaling said cloud at aninspiratory flow rate and volume adapted to deliver a portion of saidinsulin cloud to the lungs of said patient; wherein from 1 to 30 unitsof insulin are repeatably absorbed into the bloodstream of said patient.40. A method of treating diabetes mellitus in a patient in need thereof,said method comprising: (a) aerosolizing, in a hand held device, a firstpredetermined amount of insulin, which is in excess of the amount ofinsulin required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level, with a compressed gas toform a first cloud in said hand held device, said first cloud comprisinga first repeatable and controlled amount of insulin which is in excessof the amount of insulin required, in the bloodstream of said patient,to produce or maintain an acceptable serum glucose level; (b) inhalingsaid first cloud at an inspiratory flow rate and volume adapted todeliver a portion of said first cloud to the lungs of said patient,wherein insulin is absorbed into the bloodstream of said patient; and(c) repeating (a) and (b) with a second predetermined amount of insulinwhich is the same as or different from said first predetermined amountand is in excess of the amount of insulin required, in the bloodstreamof said patient, to produce or maintain an acceptable serum glucoselevel and a second repeatable and controlled amount of insulin which isthe same as or different from said first repeatable and controlledamount and is in excess of the amount of insulin required, in thebloodstream of said patient, to produce or maintain an acceptable serumglucose level.
 41. A method of treating diabetes mellitus in a patientin need thereof, said method comprising: (a) aerosolizing, in a handheld device, a first predetermined amount of insulin in the form of adry powder with a compressed gas to form a first cloud in said hand helddevice, said first predetermined amount being an amount in excess of theamount of insulin required, in the bloodstream of said patient, toproduce or maintain an acceptable serum glucose level, said first cloudcomprising a first repeatable and controlled amount of insulin which isin excess of the amount of insulin required, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level; (b)inhaling said first cloud at an inspiratory flow rate and volume adaptedto deliver a portion of said first cloud to the lungs of said patient,wherein insulin is absorbed into the bloodstream of said patient; and(c) repeating (a) and (b) with a second predetermined amount of insulinwhich is the same as or different from said first predetermined amountand is in excess of the amount of insulin required, in the bloodstreamof said patient, to produce or maintain an acceptable serum glucoselevel and a second repeatable and controlled amount of insulin which isthe same as or different from said first repeatable and controlledamount and is in excess of the amount of insulin required, in thebloodstream of said patient, to produce or maintain an acceptable serumglucose level.
 42. A method of treating diabetes mellitus in a patientin need thereof, said method comprising: (a) aerosolizing, in a handheld device, a first predetermined amount of insulin in the form of adry powder, said first predetermined amount being 2 to 10 times thatamount required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level in said patient, with acompressed gas to form a first dry cloud in said hand held device, saidfirst cloud comprising a first repeatable and controlled amount ofinsulin which is 2 to 10 times that amount required, in the bloodstreamof said patient, to produce or maintain an acceptable serum glucoselevel in said patient; (b) inhaling said first cloud at an inspiratoryflow rate and volume adapted to deliver a portion of said first cloud tothe lungs of said patient, wherein insulin is absorbed into thebloodstream of said patient; (c) repeating (a) and (b) with a secondpredetermined amount of insulin which is the same as or different fromsaid first predetermined amount and is in excess of the amount ofinsulin required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level and a second repeatable andcontrolled amount of insulin which is the same as or different from saidfirst repeatable and controlled amount and is in excess of the amount ofinsulin required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level.
 43. A method of treatingdiabetes mellitus in a patient in need thereof, said method comprising:(a) aerosolizing, in a hand held device, a first predetermined amount ofinsulin in the form of a dry powder, said first predetermined amountbeing 2 to 10 times that amount required, in the bloodstream of saidpatient, to produce or maintain an acceptable serum glucose level insaid patient, with a compressed gas to form a first dry cloud in saidhand held device, said first cloud comprising a first repeatable andcontrolled amount of insulin which is 2 to 10 times that amountrequired, in the bloodstream of said patient, to produce or maintain anacceptable serum glucose level in said patient; (b) inhaling said firstcloud at an inspiratory flow rate and volume adapted to deliver aportion of said first cloud to the lungs of said patient, wherein 1 to30 units of insulin are absorbed into the bloodstream of said patient;(c) repeating (a) and (b) with a second predetermined amount of insulinwhich is the same as or different from said first predetermined amountand is 2 to 10 times that amount of insulin required, in the bloodstreamof said patient, to produce or maintain an acceptable serum glucoselevel and a second repeatable and controlled amount of insulin which isthe same as or different from said first repeatable and controlledamount and is 2 to 10 times that amount of insulin required, in thebloodstream of said patient, to produce or maintain an acceptable serumglucose level.
 44. A method of treating diabetes mellitus in a patientin need thereof, said method comprising: (a) aerosolizing, in a handheld device, a first predetermined amount of insulin in the form of adry powder, said first predetermined amount being 2 to 300 units ofinsulin, with a compressed gas to form a first dry cloud in said handheld device, said first cloud comprising a first repeatable andcontrolled amount of insulin being 2 to 300 units of insulin; (b)inhaling said first cloud at an inspiratory flow rate and volume adaptedto deliver a portion of said first cloud to the lungs of said patient;wherein from 1 to 30 units of insulin are repeatably absorbed into thebloodstream of said patient; (c) repeating (a) and (b) with a secondpredetermined amount which is the same as or different from said firstpredetermined amount and is 2 to 300 units of insulin and a secondrepeatable and controlled amount which is the same as or different fromsaid first repeatable and controlled amount and is 2 to 300 units ofinsulin.